Bone tissue deficiencies, including poor implant-bone integration, non-union fractures, and bone loss associated with diseases such as osteoporosis, trauma, joint replacements, and tumors, have tremendous socioeconomic impact in terms of disability and related health care costs. Biomaterial-based strategies to enhance implant osseointegration and bone formation will enable the development of biologically active and integrative orthopaedic and dental implant technologies to address these pressing clinical issues. The objective of this project is to engineer biomaterials presenting cell adhesive motifs that specifically bind to integrin receptors involved in bone formation in order to promote implant osseointegration and bone repair. Our central hypothesis is that precise presentation of pro-osteogenic, integrin-specific ligands will direct osteoblastic differentiation, implant osseointegration and bone repair. We have formulated this hypothesis based on our work with two engineered integrin-specific ligands that recapitulate the secondary structure of their native ligands (triple-helical GFOGER peptide from collagen-I for a2b1 integrin, recombinant FNIII7-10 from fibronectin for a5b1 integrin) and promote osteoblastic differentiation, implant osseointegration, and repair of bone defects. Aim 1: Engineer integrin-specific coatings that enhance screw-bone integration in healthy and ovariectomized rats. Aim 2: Engineer poly(ethylene glycol)-based hydrogels presenting integrin-specific ligands as grafting templates and BMP-2 delivery vehicles for the repair of non-healing bone defects. This research is innovative because it focuses on engineering novel biomaterial coatings and hydrogels with specificity for pro-osteogenic integrins to promote bone formation and repair. This work will establish the extent to which presentation of integrin-specific ligands enhances screw-bone integration in both healthy and osteoporotic bone. Also, we will engineer novel hydrogels as grafting materials and BMP-2 delivery vehicles for enhanced repair of non-healing bone defects. Collectively, these studies will establish novel bioactive materials that enhance bone formation and implant integration for improved bone repair in various clinical applications. PUBLIC HEALTH RELEVANCE: Biomaterials play crucial roles in the treatment of bone deficiencies, but their performance is significantly limited by poor integration into bone and bone formation. We will engineer novel implant coatings and bone grafts that enhance implant-bone integration and bone repair. These materials will improve bone reconstruction procedures compared to present-day approaches.